Adenosine A2a receptor antagonists for the treatment of extra-pyramidal syndrome and other movement disorders

ABSTRACT

There is disclosed a method for the treatment or prevention of Extra Pyramidal syndrome (EPS), dystonia, restless leg syndrome (RLS) or periodic leg movement in sleep (PLMS) comprising the administration of an adenosine A2a receptor antagonist, alone or in combination with other agents useful for treating EPS, dystonia, RLS or PLMS.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. ProvisionalApplication 60/435,321, filed Dec. 19, 2002.

FIELD OF THE INVENTION

[0002] The present invention relates to the use of adenosine A_(2a)receptor antagonists for the treatment of a variety of neurologicalsyndromes involving the extra-pyramidal motor system (i.e.Extra-Pyramidal Syndrome) that occur following the acute and chronic useof almost all antipsychotic drugs. The invention also relates to the useof adenosine A_(2a) receptor antagonists for the treatment of otherabnormal movement disorders such as restless leg syndrome (RLS) andperiodic limb movement in sleep (PLMS).

BACKGROUND OF THE INVENTION

[0003] Extra-Pyramidal Syndrome (EPS) is a collective term for a seriesof adverse neurological reactions associated with the use ofantipsychotic drugs. There are six different categories of EPS-relatedneurological syndromes of which four, dystonia, akathisia,pseudoparkinsonism (parkinsonian syndrome), and tardive dyskinesia, areparticularly prevalent in patients taking antipsychotic medication.Dystonia is a painful spasm of the muscle groups of, in particular, theneck, jaw, back, pharynx, and larynx. It is most common in young malesbeing treated with antipsychotic drugs, but can also be associated withthe use of cocaine, tricyclic antidepressants, lithium andanticonvulsants such as phenytoin and carbamazepine. Pseudoparkinsonismmanifests itself as akinesia (rigidity, stiffness and slow voluntarymotion, stooped, shuffling walk) and tremor and these symptoms developwithin weeks or months after initiation of therapy. Akathisia manifestsitself as strong, subjective inner feelings of distress or discomfortcharacterized by motor restlessness. Often mistaken for agitation oranxiety, this common syndrome is frequently under-diagnosed and is theleast responsive to treatment. Tardive dyskinesia is a late-appearingsyndrome associated with chronic use of neuroleptic drugs. It occursmore frequently in older patients and is characterized by stereotypical,repetitive, involuntary, quick choreiform movements of the face,eyelids, mouth, tongue, extremities and trunk.

[0004] EPS is more prevalent with the use of typical antipsychoticagents but has also been reported with the use of atypical agents.Typical antipsychotics include loxapine, haloperidol, chlorpromazine,prochlorperazine and thiothixene. Atypical antipsychotics includeclozapine, olanzapine, loxapine, quetiapine, ziprasidone andrisperidone.

[0005] Akathisia is also a characteristic of RLS and PLMS, as well asPLMD (periodic leg (or limb) movement disorder). RLS is a commondisorder that causes patients to have an irresistible and unpleasantdesire to move their legs; it usually manifests during periods ofinactivity and/or at night, and can disturb sleep. Patients who do nothave the typical RLS symptoms, but who do exhibit periodic leg movementsthat adversely impact sleep, are diagnosed with PLMS. Treatments for RLSand PLMS have included levodopa/carbidopa, levodopa/benserazide,dopamine agonists such as pramipexole and ropinerole, benzodiazepines,opioids, anticonvulsants and iron (ferrous sulfate). RLS and PLMS havebeen extensively described in the literature, for example by Saletu etal, Neuropsychobiology, 41, 4 (2000), p. 190-9.

[0006] The purine nucleotide, adenosine, is known to be an endogenousmodulator of a number of physiological functions in the central (CNS)and peripheral nervous systems.

[0007] Adenosine exerts its biological actions through a class ofmembrane specific receptors which belong to the super family ofreceptors coupled with G proteins. Biochemical and pharmacologicalstudies, together with advances in molecular biology, have allowed theidentification of at least four subtypes of adenosine receptors: A₁,A_(2a), A_(2b) and A₃. Analogs of adenosine able to interact asantagonists with the A₁, A_(2a), A_(2b) and A₃ receptors have also beenidentified.

[0008] In the CNS, data has shown that A_(2a) receptors are present inhigh density in the basal ganglia, known to be important in the controlof fine motor movement. Moreover, selective antagonists for the A_(2a)receptor are of pharmacological interest because of their demonstratedefficacy in reducing motor impairment thereby improving function inneurodegenerative diseases such as Parkinson's disease and relatedmovement disorders (e.g. Huntington's Disease). A_(2a) antagonistsappear to demonstrate a reduced side-effect liability (e.g. nodyskinesia) compared to current dopaminergic therapies resulting in animproved therapeutic index. A_(2a) antagonists may also haveantidepressant properties and stimulate cognitive functions. Somexanthine-related compounds have been found to be A₁ receptor selectiveantagonists, and xanthine and non-xanthine compounds have been found tohave high A_(2a) affinity with varying degrees of A_(2a) vs. A₁selectivity. Adenosine A_(2a) receptor antagonists have been disclosedpreviously, for example in WO 95/01356 and U.S. Pat. No. 6,630,475.

SUMMARY OF THE INVENTION

[0009] This invention relates to a method for the treatment orprevention of Extra-Pyramidal Syndrome (e.g., dystonia, akathisia,pseudoparkinsonism and tardive dyskinesia) comprising administering atherapeutically effective amount of an adenosine A_(2a) receptorantagonist to a patient in need thereof. In particular, this method isfor the treatment or prevention of EPS in patients treated with anantipsychotic agent that has the side effect of inducing EPS. Theadenosine A_(2a) receptor antagonist can be administered after thesymptoms of EPS have manifested, or an adenosine A_(2a) receptorantagonist can be administered at the onset of administering anantipsychotic agent in order to prevent EPS from occurring. Theinvention, therefore, also includes a method of treating or preventingEPS induced by an antipsychotic agent comprising administering acombination of an antipsychotic agent and an adenosine A_(2a) antagonistto a patient in need thereof. More particularly, the invention relatesto the method of using of certain adenosine A_(2a) antagonists for themonotherapy or the combined therapy.

[0010] The invention also relates to the treatment of primary(idiopathic) dystonia, and to the treatment or prevention of dystonia inpatients who exhibit dystonia as a result of treatment with a tricyclicantidepressant, lithium or an anticonvulsant, or who have used cocaine,comprising administering a therapeutically effective amount of anadenosine A_(2a) receptor antagonist to a patient in need thereof. Whendystonia is caused by treatment with a tricyclic antidepressant, lithiumor an anticonvulsant, the adenosine A_(2a) receptor antagonist can beadministered after the symptoms of dystonia have manifested, or anadenosine A_(2a) receptor antagonist can be administered at the onset ofadministering a tricyclic antidepressant, lithium or an anticonvulsantin order to prevent dystonia from occurring. The invention, therefore,also includes a method of treating or preventing dystonia induced by atricyclic antidepressant, lithium or an anticonvulsant comprisingadministering a combination of an adenosine A_(2a) antagonist and atricyclic antidepressant, lithium or an anticonvulsant to a patient inneed thereof.

[0011] The invention also relates to the treatment of RLS or PLMS,comprising administering to a patient in need thereof a therapeuticallyeffective amount of an adenosine A_(2a) receptor antagonist. Theinvention also comprises a method of treating RLS or PLMS comprisingadministering a combination of an adenosine A_(2a) antagonist withanother agent useful in treating RLS or PLMS, such aslevodopa/carbidopa, levodopa/benserazide, a dopamine agonist, abenzodiazepine, an opioid, an anticonvulsant or iron, to a patient inneed thereof.

[0012] In another aspect, this invention relates to a kit comprising, inseparate containers in a single package, pharmaceutical compositions foruse in combination to treat or prevent EPS caused by treatment withantipsychotic agent, wherein one container comprises a pharmaceuticalcomposition comprising an effective amount of an adenosine A_(2a)receptor antagonist in a pharmaceutically acceptable carrier, andwherein a separate container comprises a pharmaceutical compositioncomprising an effective amount of an antipsychotic agent.

[0013] In another aspect, this invention relates to a kit comprising, inseparate containers in a single package, pharmaceutical compositions foruse in combination to treat or prevent dystonia caused by treatment witha tricyclic antidepressant, lithium or an anticonvulsant, wherein onecontainer comprises a pharmaceutical composition comprising an effectiveamount of an adenosine A_(2a) receptor antagonist in a pharmaceuticallyacceptable carrier, and wherein a separate container comprises apharmaceutical composition comprising an effective amount of a tricyclicantidepressant, lithium or an anticonvulsant.

[0014] In another aspect, this invention relates to a kit comprising, inseparate containers in a single package, pharmaceutical compositions foruse in combination to treat RLS or PLMS, wherein one container comprisesa pharmaceutical composition comprising an effective amount of anadenosine A_(2a) receptor antagonist in a pharmaceutically acceptablecarrier, and wherein a separate container comprises a pharmaceuticalcomposition comprising an effective amount of levodopa/carbidopa,levodopa/benserazide, a dopamine agonist, a benzodiazepine, an opioid,an anticonvulsant or iron.

[0015] The invention also relates to the use of an adenosine A_(2a)receptor antagonist for the preparation of a medicament for treating orpreventing EPS, dystonia, RLS or PLMS, alone or in combination with theother agents discussed above.

DETAILED DESCRIPTION OF THE DRAWINGS

[0016] A more complete understanding of the invention may be obtained byreading the following description in conjunction with the appendedfigures relating to haloperidol-induced EPS in Cebus apella monkeys.

[0017]FIG. 1A illustrates the effect of Compound A (1-30 mg/kg, p.o.) onmaximum EPS score.

[0018]FIG. 1B represents the mean delay in onset of EPS for eachtreatment group compared to a vehicle control group.

DETAILED DESCRIPTION OF THE INVENTION

[0019] Any adenosine A_(2a) receptor antagonist is contemplated for usein the method of this invention. Suitable adenosine A_(2a) receptorantagonists useful in the method of the invention can be identified bythe binding assay described below. Specific examples of suitableadenosine A_(2a) antagonists include the compounds disclosed in severalpatents and patent applications, e.g. WO 95/01356; U.S. Pat. No.5,565,460; U.S. Pat. No. 6,630,475 B2; U.S. Pat. No. 5,935,964; WO03/032996; WO 03/048165; WO 03/048164; WO 03/048163; and WO 01/02409.Specifically, these patents and applications disclose the followingcompounds.

[0020] U.S. Pat. No. 6,630,475 B2 discloses compounds having thestructural formula I

[0021] or a pharmaceutically acceptable salt thereof, wherein

[0022] R is R¹-furanyl, R¹-thienyl, R¹-pyridyl, R¹-pyridyl N-oxide,R¹-oxazolyl, R¹⁰-phenyl, R¹-pyrrolyl or C₄-C₆ cycloalkenyl;

[0023] X is C₂-C₆ alkylene or —C(O)CH₂—;

[0024] Y is —N(R²)CH₂CH₂N(R³)—, —OCH₂CH₂N(R²)—, —O—, —S—, —CH₂S—,—(CH₂)₂—NH—, or

[0025] and

[0026] Z is R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl, R⁵-heteroaryl,diphenylmethyl, R⁶—C(O)—, R⁶—SO₂—, R⁶—OC(O)—, R⁷—N(R⁸)—C(O)—,R⁷—N(R⁸)—C(S)—,

[0027] phenyl-CH(OH)—, or phenyl-C(═NOR²)—; or when Q is

[0028] Z is also phenylamino or pyridylamino; or

[0029] Z and Y together are

[0030] R¹ is 1 to 3 substituents independently selected from hydrogen,C₁-C₆-alkyl, —CF₃, halogen, —NO₂, —NR¹²R¹³, C₁-C₆ alkoxy, C₁-C₆alkylthio, C₁-C₆ alkylsulfinyl, and C₁-C₆ alkylsulfonyl;

[0031] R² and R³ are independently selected from the group consisting ofhydrogen and C₁-C₆ alkyl;

[0032] m and n are independently 2-3;

[0033] Q is

[0034] R⁴ is 1-2 substituents independently selected from the groupconsisting of hydrogen and C₁-C₆alkyl, or two R⁴ substituents on thesame carbon can form ═O;

[0035] R⁵ is 1 to 5 substituents independently selected from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy,—CN, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃, acetyl, —NO₂,hydroxy(C₁-C₆)alkoxy, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy,di-((C₁-C₆)-alkoxy)(C₁-C₆)alkoxy,(C₁-C₆)-alkoxy(C₁-C₆)alkoxy-(C₁-C₆)-alkoxy, carboxy(C₁-C₆)-alkoxy,(C₁-C₆)-alkoxycarbonyl(C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl(C₁-C₆)alkoxy,di-((C₁-C₆)alkyl)amino(C₁-C₆)alkoxy, morpholinyl, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-SO—(C₁-C₆)alkoxy, tetrahydropyranyloxy,(C₁-C₆)alkylcarbonyl(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)alkylcarbonyloxy(C₁-C₆)-alkoxy, —SO₂NH₂, phenoxy,

[0036] or adjacent R⁵ substituents together are —O—CH₂—O—, —O—CH₂CH₂—O—,—O—CF₂—O— or —O—CF₂CF₂—O— and form a ring with the carbon atoms to whichthey are attached;

[0037] R⁶ is (C₁-C₆)alkyl, R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl, thienyl,pyridyl, (C₃-C₆)-cycloalkyl, (C₁-C₆)alkyl-OC(O)—NH—(C₁-C₆)alkyl-,di-((C₁-C₆)alkyl)aminomethyl, or

[0038] R⁷ is (C₁-C₆)alkyl, R⁵-phenyl or R⁵-phenyl(C₁-C₆)alkyl;

[0039] R⁸ is hydrogen or C₁-C₆ alkyl; or R⁷ and R⁸ together are—(CH₂)_(p)-A-(CH₂)_(q), wherein p and q are independently 2 or 3 and Ais a bond, —CH₂—, —S— or —O—, and form a ring with the nitrogen to whichthey are attached;

[0040] R⁹ is 1-2 groups independently selected from hydrogen, C₁-C₆alkyl, hydroxy, C₁-C₆ alkoxy, halogen, —CF₃ and(C₁-C₆)alkoxy(C₁-C₆)alkoxy;

[0041] R¹⁰ is 1 to 5 substituents independently selected from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy,—CN, —NH₂, C₁-C₆alkylamino, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃ and—S(O)₀₋₂(C₁-C₆)alkyl;

[0042] R^(11 is H, C) ₁-C₆ alkyl, phenyl, benzyl, C₂-C₆ alkenyl, C₁-C₆alkoxy(C₁-C₆)alkyl, di-((C₁-C₆)alkyl)amino(C₁-C₆)alkyl,pyrrolidinyl(C₁-C₆)alkyl or piperidino(C₁-C₆)alkyl;

[0043] R¹² is H or C₁-C₆ alkyl; and

[0044] R¹³ is (C₁-C₆)alkyl-C(O)— or (C₁-C₆)alkyl-SO₂—.

[0045] Preferred compounds of formula I are those wherein R isR¹-furanyl, R¹-thienyl, R¹-pyrrolyl or R¹⁰-phenyl, more preferablyR¹-furanyl. R¹ is preferably hydrogen or halogen. Another group ofpreferred compounds is that wherein X is alkylene, preferably ethylene.Y is preferably

[0046] wherein Q is

[0047] with Q preferably being nitrogen. Preferably, m and n are each 2,and R⁴ is H. A preferred definition for Z is R⁵-phenyl, R⁵-heteroaryl,R⁶—C(O)— or R⁶—SO₂—. R⁵ is preferably H, halogen, alkyl, alkoxy,hydroxyalkoxy or alkoxyalkoxy. R⁶ is preferably R⁵-phenyl.

[0048] Preferred specific compounds of formula I are those of theformula IA

[0049] wherein R and Z-Y are as defined in the following table: Z—Y— R

[0050] Other useful adenosine A_(2a) receptor antagonists include thosedisclosed in WO 95/01356 as compounds having the structural formula II

[0051] wherein:

[0052] A is pyrazole, imidazole or a triazole ring;

[0053] R is hydrogen; C₁-C₈ alkyl; C₃-C₇ alkenyl; C₃-C₇ alkynyl; C₃-C₇cycloalkyl; C₁-C₅ alkyl substituted with one or more halogen atoms,hydroxy groups, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl, groups of formula—NR₁R₂, —CONR₁R₂; aryl optionally substituted with halogen atoms, C₁-C₄alkoxy groups, C₁-C₄ alkyl, nitro, amino, cyano, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, carboxy, carboxyamido; C₇-C₁₀ aralkyl in which the arylmoiety can be substituted with one or more of the substituents indicatedabove for the aryl group; a group of formula —(CH₂)_(m)-Het, wherein Hetis a 5-6 membered aromatic or non aromatic heterocyclic ring containingone or more heteroatoms selected from N, O, S and m is an integer from 1to 5;

[0054] R₁, R₂ which are the same or different, are hydrogen, C₁-C₅alkyl, C₇-C₁₀ aralkyl, phenyl, or taken together with the nitrogen theyare linked to, form an azetidine ring or a 5-6 membered heterocyclicring containing one or more heteroatoms such as N, O, S and n is aninteger from 2 to 5.

[0055] Preferably, compounds of formula II are those wherein R ishydrogen, C₁-C₈ alkyl, aryl or C₇-C₁₀ aralkyl optionally substituted,preferably with halogen atoms.

[0056] U.S. Pat. No. 5,935,964 discloses useful adenosine A_(2a)receptor antagonist compounds having the structural formula III

[0057] wherein A is pyrazole, imidazole or triazole ring;

[0058] R is

[0059] R₁ and R₂, which are the same or different, are H, OH, halogen,C₁-C₄ alkoxy, C₁-C₄ alkyl, nitro, amino, cyano, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, carboxy or carboxamido; or the OH group, together with oneof R₁ or R₂, or R₁ and R₂, can form a methylenedioxy group —O—CH₂—O—;and

[0060] n is an integer from 0-4.

[0061] Preferred compounds of formula III are those wherein A ispyrazolo[4,3-e] or 1,2,3-triazolo[5,4-e].

[0062] U.S. Pat. No. 5,565,460 discloses useful adenosine A_(2a)receptor antagonist compounds having the structural formulas IVA andIVB, wherein formula IVA is

[0063] wherein R¹ represents hydrogen, substituted or unsubstitutedlower alkyl, or substituted or unsubstituted lower alkanoyl;

[0064] R² represents hydrogen, substituted or unsubstituted lower alkyl,substituted or unsubstituted lower alkenyl, substituted or unubstitutedcycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted aralkyl, or a substituted or unsubstituted heterocyclicgroup;

[0065] R³ represents a substituted or unsubstituted heterocyclic group;

[0066] X represents a single bond, O, S, S(O), S(O)₂, or NR⁴ (in whichR⁴ represents hydrogen, or substituted or unsubstituted lower alkyl; orR² and NR⁴ are combined to form a substituted or unsubstituted 4 to6-membered saturated heterocyclic group): and

[0067] A represents N or CR⁵ (in which R⁵ represents hydrogen, or asubstituted or unsubstituted lower alkyl); and

[0068] wherein formula IVB is

[0069] wherein R⁶ represents substituted or unsubstituted aryl, or asubstituted or unsubstituted heterocyclic group;

[0070] Y represents O, S, or NR⁷ (in which R⁷ represents substituted orunsubstituted lower alkyl, substituted or unubstituted cycloalkyl, orsubstituted or unsubstituted aryl);

[0071] R⁸ represents hydrogen, substituted or unsubstituted lower alkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedlower alkynyl, substituted or unubstituted cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted aralkyl, or asubstituted or unsubstituted heterocyclic group; and

[0072] B and the adjacent two carbon atoms are combined to form asubstituted or unsubstituted, partially saturated or unsaturated,monocyclic or bicyclic, carbocyclic or heterocyclic group.

[0073] WO 03/032996 discloses useful adenosine A_(2a) receptorantagonist compounds having the structural formula V

[0074] or a pharmaceutically acceptable salt thereof, wherein

[0075] R is R¹-heteroaryl, R¹⁰-phenyl, C₄-C₆ cycloalkenyl, —C(═CH₂)CH₃,—C≡C—CH₃, —C≡C—CH₂—OR² , —CH═C(CH₃)₂,

[0076] X is C₁-C₆ alkylene, —C(O)CH₂— or —C(O)N(R²)CH₂—;

[0077] Y is —N(R²)CH₂CH₂N(R³)—, —OCH₂CH₂N(R²)—, —O—, —S—, —CH₂S—,—(CH₂)₂₋₃—N(R²)—, R⁵-divalent heteroaryl,

[0078] and

[0079] Z is R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl, R⁵-heteroaryl, R⁵-bicyclicheteroaryl, R⁵-benzofused heteroaryl, diphenylmethyl or R⁶—C(O)—;

[0080] or when Y is

[0081] Z is also R⁶—SO₂—, R⁷—N(R⁸)—C(O)—, R⁷—N(R⁸)—C(S)— or R⁶OC(O)—;

[0082] or when Q is

[0083] Z is also phenylamino or pyridylamino;

[0084] or Z and Y together are

[0085] or Y and Z together form a piperidinyl or pyrrolidinyl ring fusedto a monocyclic or bicyclic aryl or a monocyclic or bicyclic heteroarylring wherein X is attached to the N atom of the piperidinyl orpyrrolidinyl ring;

[0086] R¹ is 1 to 3 substituents independently selected from hydrogen,C₁-C₆-alkyl, —CF₃, halogen, —NO₂, —NR¹²R¹³, C₁-C₆ alkoxy, C₁-C₆alkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, —COOR⁷ or—C(O)NR²R³;

[0087] R² and R³ are independently selected from the group consisting ofhydrogen and C₁-C₆ alkyl;

[0088] m and n are independently 2-3;

[0089] p and q are independently 0-2;

[0090] Q and Q¹ are independently selected from the group consisting of

[0091] provided that at least one of Q and Q¹ is

[0092] R⁴ is 1-2 substituents independently selected from the groupconsisting of hydrogen, C₁-C₆alkyl, R¹-aryl and R¹-heteroaryl, or two R⁴substituents on the same carbon can form ═O;

[0093] R⁵ is 1 to 5 substituents independently selected from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy,—CN, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃, acetyl, —NO₂,hydroxy(C₁-C₆)alkoxy, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy,di-((C₁-C₆)-alkoxy)(C₁-C₆)alkoxy,(C₁-C₆)-alkoxy(C₁-C₆)alkoxy-(C₁-C₆)-alkoxy, carboxy(C₁-C₆)—alkoxy,(C₁-C₆)-alkoxycarbonyl(C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl(C₁-C₆)alkoxy,di-((C₁-C₆)alkyl)amino(C₁-C₆)alkoxy, morpholinyl, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkoxy, tetrahydropyranyloxy,(C₁-C₆)alkylcarbonyl(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)alkylcarbonyloxy(C₁-C₆)-alkoxy, —SO₂NH₂, phenoxy,

[0094] (R²O)₂—P(O)—CH₂—O— and (R²O)₂—P(O)—; or adjacent R⁵ substituentstogether are —O—CH₂—O—, —O—CH₂CH₂—O—, —O—CF₂—O— or —O—CF₂CF₂—O—and forma ring with the carbon atoms to which they are attached;

[0095] R⁶ is (C₁-C₆)alkyl, R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl, thienyl,pyridyl, (C₃-C₆)-cycloalkyl, (C₁-C₆)alkyl-OC(O)—NH—(C₁-C₆)alkyl-,di-((C₁-C₆)alkyl)aminomethyl, or

[0096] R⁷ is (C₁-C₆)alkyl, R⁵-phenyl or R⁵-phenyl(C₁-C₆)alkyl;

[0097] R⁸ is hydrogen or C₁-C₆ alkyl; or R⁷ and R⁸ together are—(CH₂)_(p)-A-(CH₂)_(q), wherein p and q are independently 2 or 3 and Ais a bond, —CH₂—, —S— or —O—, and form a ring with the nitrogen to whichthey are attached;

[0098] R⁹ is 1-2 substituents independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, halogen,—CF₃ and (C₁-C₆)alkoxy-(C₁-C₆)alkoxy;

[0099] R¹⁰ is 1 to 5 substituents independently selected from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy,—CN, —NH₂, C₁-C₆alkylamino, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃,—S(O)₀₋₂(C₁-C₆)alkyl and —CH₂—SO₂-phenyl;

[0100] R¹¹ is H, C₁-C₆ alkyl, phenyl, benzyl, C₂-C₆ alkenyl, C₁-C₆alkoxy(C₁-C₆)alkyl, di-((C₁-C₆)alkyl)amino(C₁-C₆)alkyl,pyrrolidinyl(C₁-C₆)alkyl or piperidino(C₁-C₆)alkyl;

[0101] R¹² is H or C₁-C₆ alkyl;

[0102] R¹³ is H, (C₁-C₆)alkyl-C(O)— or (C₁-C₆)alkyl-SO₂—;

[0103] R¹⁴ is H, halogen, C₁-C₆ alkyl, hydroxy(C₁-C₆)alkyl, C₁-C₆alkoxy(C₁-C₆)alkyl, thio(C₁-C₆)alkyl, (C₁-C₆)alkylthio(C₁-C₆)alkyl orNR²R³—(C₁-C₆)alkyl; and

[0104] R¹⁵ is H, halogen, C₁-C₆ alkyl or C₁-C₆ alkoxy.

[0105] Preferred compounds of formula V are those wherein R isR¹-furanyl, R¹-thienyl, R¹-pyrrolyl, R¹-pyridyl or R¹⁰-phenyl, morepreferably R¹-furanyl or R¹⁰-phenyl. R¹ is preferably hydrogen orhalogen. R¹⁰ is preferably hydrogen, halogen, alkyl or —CF₃. Anothergroup of preferred compounds is that wherein X is alkylene, preferablyethylene. Y is preferably

[0106] wherein Q is

[0107] with Q preferably being nitrogen. Preferably, m and n are each 2,and R⁴ is H. A preferred definition for Z is R⁵-phenyl or R⁵-heteroaryl.R⁵ is preferably H, halogen, alkyl, alkoxy, hydroxyalkoxy oralkoxyalkoxy. R⁶ is preferably R⁵-phenyl.

[0108] Preferred specific compounds of formula V are those of theformula VA

[0109] wherein R and Z-Y are as defined in the following table: Z—Y— R

[0110] WO 03/048165 discloses useful adenosine A_(2a) receptorantagonist compounds having the structural formula VI

[0111] or a pharmaceutically acceptable salt or solvate of saidcompound, wherein:

[0112] R is selected from the group consisting of R¹-furanyl-,R¹-thienyl-, R¹-pyridyl-, R¹-oxazolyl-, R¹-pyrrolyl- and R²-aryl-;

[0113] X is —(CH₂)_(n)—;

[0114] Y is a piperidinyl, pyrrolidinyl or azepanyl group with an arylor heteroaryl moiety fused to two adjacent carbon atoms on Y, wherein Xis attached to the N atom of the piperidinyl, pyrrolidinyl or azepanylgroup;

[0115] Q is 1-4 substituents, which can be the same or different, andare independently selected from the group consisting of hydrogen,cycloalkyl, cycloheteroalkyl, amino, aryl, aralkyl, heteroaryl, alkyl,CF₃, CN, halogen, NO₂, alkoxy, alkoxyalkoxy, cycloalkylalkoxy, acyloxy,alkylamino, acylamino, alkylsulfonamino, alkylaminosulfonyl,dialkylaminosulfonyl, NH₂SO₂—, and hydroxy;

[0116] n is 1 to 4;

[0117] R¹ is 1-3 substituents, which may be the same or different, andare independently selected from the group consisting of hydrogen, alkyl,CF₃, halogen and NO₂; and

[0118] R² is 1-3 substituents, which may be the same or different, andare independently selected from the group consisting of hydrogen, alkyl,CF₃, halogen, NO₂, alkoxy, acyloxy, alkylamino, acylamino,alkylsulfonamido, alkylaminosulfonyl, dialkylaminosulfonyl,aminosulfonyl, and hydroxyl.

[0119] In a preferred embodiment of compounds of formula VI, Y is

[0120] wherein A₁ is N—X, and A² and A³ each are CR⁴R⁵, or

[0121] A¹ and A³ each are CR⁴R⁵, and A² is N—X, or

[0122] A¹ and A² each are CR⁴R⁵, and A³ is N—X;

[0123] A⁴ is CR⁴R⁵;

[0124] Z¹, Z², Z³ and Z⁴, which can the same or different, are eachindependently selected from the group consisting of N and CR³, providedthat 0-2 of Z¹, Z², Z³ or Z⁴ are N and the remainder are CR³;

[0125] Z⁵ is NR⁵, O, S or CR⁴R⁵;

[0126] Z⁶ is N or CR³;

[0127] Z⁷ is N or CR³;

[0128] m is an integer from 0 to 2;

[0129] R³is selected from the group consisting of hydrogen, cycloalkyl,amino, aryl, heteroaryl, C₁-C₆-alkyl, CF₃, CN, halogen, NO₂,C₁-C₆-alkoxy, C₁-C₆-acyloxy, C₁-C₆-alkylamino, C₁-C₆-acylamino,C₁-C₆-alkylsulfonamino, C₁-C₆-alkylaminosulfonyl,C₁-C₆-dialkylaminosulfonyl, NH₂—SO₂—, and hydroxy;

[0130] R⁴ is selected from the group consisting of hydrogen,hydroxyalkyl, aryl, aralkyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, CF₃, CN,halogen, hydroxy, and NO₂; and

[0131] R⁵ is hydrogen or C₁-C₆ alkyl.

[0132] Preferred specific examples of compounds of formula VI includecompounds of the formula:

[0133] WO 03/048164 discloses useful adenosine A_(2a) receptorantagonist compounds having the structural formula VII

[0134] or a pharmaceutically acceptable salt or solvate thereof;wherein:

[0135] R is selected from the group consisting of R⁴-heteroaryl,R⁵-phenyl, (C₄-C₆)cycloalkenyl, —C(═CH₂)CH₃, —C≡C—CH₃,

[0136] —CH═C(CH₃)₂,

[0137] and —CH═CH—CH₃;

[0138] R² is selected from the group consisting of —W—X,—NR¹⁹(CH₂)_(m)—W—X, and —NR¹⁹CH(CH₃)—W—X, or

[0139] R² is selected from the group consisting of alkyl, alkenyl and—NR¹⁸R¹⁹, wherein said alkyl, alkenyl or —NR¹⁸R¹⁹ is optionallysubstituted by —W—X;

[0140] R³ is selected from the group consisting of H, halo, alkyl,trifluoromethyl, alkoxy, alkoxyalkyl, hydroxyalkyl, alkylamino,alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, aminoalkyl, aryl,heteroaryl, and CN;

[0141] R⁴ is 1 to 3 substituents, which can be the same or different,and are independently selected from the group consisting of hydrogen,(C₁-C₆)-alkyl, —CF₃, halogen, —NO₂, —NR¹⁵R¹⁶, (C₁-C₆)alkoxy,(C₁-C₆)alkylthio, (C₁-C₆)alkylsulfinyl, (C₁-C₆)alkylsulfonyl, —COOR¹⁷and —C(O)NR⁶R^(7;)

[0142] R⁵ is 1 to 5 substituents, which can be the same or different,and are independently selected from the group consisting of hydrogen,halogen, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, —CN, —NH₂,(C₁-C₆)alkylamino, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃,—S(O)₀₋₂(C₁-C₆)alkyl and —CH₂—SO₂-phenyl;

[0143] R⁶ and R⁷, which can be the same or different, are eachindependently selected from the group consisting of hydrogen and(C₁-C₆)alkyl;

[0144] R⁸ is 1 to 5 substituents, which can be the same or different,and are independently selected from the group consisting of hydrogen,halogen, (C₁-C₆)alkyl, hydroxy, C₁-C₆ alkoxy, —CN, amino,di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃, acetyl, —NO₂, hydroxy(C₁-C₆)alkoxy,(C₁-C₆)-alkoxy(C₁-C₆)alkoxy, di-((C₁-C₆)-alkoxy)(C₁-C₆)alkoxy,(C₁-C₆)-alkoxy(C₁-C₆)alkoxy-(C₁-C₆)-alkoxy, carboxy(C₁-C₆)-alkoxy,(C₁-C₆)-alkoxycarbonyl(C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl(C₁-C₆)alkoxy,di-((C₁-C₆)alkyl)amino(C₁-C₆)alkoxy, morpholinyl, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkoxy, tetrahydropyranyloxy,(C₁-C₆)alkylcarbonyl(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)alkylcarbonyloxy(C₁-C₆)-alkoxy, —SO₂NH₂, phenoxy,

[0145] —O—CH₂—P(O)(OR⁶)₂,— and —P(O)(OR⁶)₂; or

[0146] adjacent R⁸ substituents together are —O—CH₂—O—, —O—CH₂CH₂—O—,—O—CF₂—O—or

[0147] —O—CF₂CF₂—O— and form a ring with the carbon atoms to which theyare attached;

[0148] R⁹ is selected from the group consisting of (C₁-C₆)alkyl,R⁸-aryl-, R⁸-aryl(C₁-C₆)alkyl-, thienyl, pyridyl, (C₃-C₆)-cycloalkyl,(C₁-C₆)alkyl-OC(O)—NH—(C₁-C₆)alkyl-, di-((C₁-C₆)alkyl)aminomethyl,cycloheteroalkyl(C₁-C₆)alkyl, aryloxy(C₁-C₆)alkyl, alkoxy(C₁-C₆)alkyland

[0149] R¹⁰ is 1-2 substituents, which can be the same or different, andare independently selected from the group consisting of hydrogen,(C₁-C₆)alkyl, R⁵-aryl and R⁴-heteroaryl, or two R¹⁰ substituents on thesame carbon can form ═O;

[0150] R¹¹ is hydrogen or (C₁-C₆)alkyl; —C(O)alkyl, or R¹⁷ and R¹¹ takentogether are —(CH₂)_(p)-A-(CH₂)_(q), wherein p and q are eachindependently 2 or 3 and A is selected from the group consisting of abond, —CH₂—, —S— and —O—, and form a ring with the nitrogen to whichthey are attached;

[0151] R¹² is 1-2 substituents, which can be the same or different, andare independently selected from the group consisting of hydrogen,(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halogen, and —CF₃;

[0152] R¹³ is selected from the group consisting of H, (C₁-C₆)alkyl,phenyl, benzyl, (C₂-C₆)alkenyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,di-((C₁-C₆)alkyl)amino(C₁-C₆)alkyl, pyrrolidinyl(C₁-C₆)alkyl andpiperidino(C₁-C₆)alkyl;

[0153] R¹⁴ is selected from the group consisting of H, halogen,(C₁-C₆)alkyl or (C₁-C₆)alkoxy;

[0154] R¹⁵ is selected from the group consisting of H and (C₁-C₆)alkyl;

[0155] R¹⁶ is selected from the group consisting of H,(C₁-C₆)alkyl-C(O)— and (C₁-C₆)alkyl-SO₂—;

[0156] R¹⁷ is selected from the group consisting of (C₁-C₆)alkyl,(C₁-C₆)hydroxyalkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, allyl, propargyl,R⁸-heteroaryl-, R⁸-aryl- and R⁸-aryl(C₁-C₆)alkyl-;

[0157] R¹⁸ is selected from the group consisting of a bond, —CH₂—,—CH(OH)—, —CH(CH₃)—, —C(CH₃)_(n)—, —(CH₂)_(n)—, and —O(CH₂)_(n)—,

[0158] R¹⁹ is selected from the group consisting of H, (C₁-C₆)alkyl,(C₁-C₆)alkyl(C₁-C₆)cycloalkyl, (C₁-C₆)cycloalkyl(C₁-C₆)alkyl and(C₁-C₆)alkoxy(C₁-C₆)alkyl;

[0159] Q and Q¹ can be the same or different and are each independentlyselected from the group consisting of

[0160] m and n are each independently 1-3;

[0161] p and q are each independently 0-2;

[0162] s is 0-4;

[0163] W is aryl or heteroaryl having 1-3 heteroatoms, which can be thesame or different, and are independently selected from the groupconsisting of N, O and S, and wherein said aryl or heteroaryl isoptionally substituted with 1-3 substituents, which can be the same ordifferent, and are independently selected from the group consisting ofalkyl, aryl, alkylcycloalkyl, halo, hydroxy, hydroxyalkyl, alkoxy,alkylalkoxy, alkoxyalkoxy, —NR⁶R⁷, (C₂-C₆)alkene, and —CN, or

[0164] X is selected from the group consisting of H, NH₂,—N(R⁶)(CH₂)_(s)-aryl, —N(R⁶)(CH₂)_(s)-heteroaryl, —N(R⁶)(CH₂)_(m+1)—OH,and —N(CH₃)₂, or

[0165] X is —R¹⁸—Y-Z;

[0166] Y is selected from the group consisting of —N(R⁶)CH₂CH₂N(R⁷)—,—N(R⁶)(CH₂)_(n)aryl, —OCH₂CH₂N(R⁶)—, —O—, —S—, —CH₂S—, —(CH₂)₂₋₃—N(R⁶)—,R⁸-divalent heteroaryl,

[0167] Z is selected from the group consisting of H, alkyl, alkoxyalkyl,R⁸-aryl-, R⁸-aryl(C₁-C₆)alkyl-, R⁸-heteroaryl-, R⁸-bicyclicalkyl-,aminoalkyl, alkylamino, NH₂, —N—(R⁶)(CH₂),-aryl,—N(R⁶)(CH₂)_(s)-heteroaryl, —N(R₆)C(O)OR¹⁷, alkylcycloheteroalkyl,cycloheteroalkyl, cycloheteroalkylalkyl, alkoxycycloheteroalkyl,heteroaryl; R⁸-benzofused heteroaryl-, diphenylmethyl and R⁹—C(O)—; or

[0168] when Y is

[0169] Z can also be —OH, R⁹—SO₂—, R¹⁷—N(R¹¹)(CH₂)_(s)—C(O)—,R¹⁷—OC(O)—, R¹⁷—O(CH₂)_(n)C(O)—, benzofused heteroaryl(CH₂)_(n)C(O)—,benzofused heteroaryl(CH₂)_(n)— or R¹⁷—N(R¹¹)—C(S)—; or

[0170] when Q is

[0171] Z can also be R¹⁷R¹¹N—, phenylamino or pyridylamino; or

[0172] Z and Y taken together are selected from the group consisting of

[0173] Preferred compounds of formula VII are those having the followingstructures:

[0174] WO 03/048163 discloses useful adenosine A_(2a) receptorantagonist compounds having the structural formula VIII

[0175] or a pharmaceutically acceptable salt thereof, wherein:

[0176] A is C(R¹) or N;

[0177] R¹ and R^(1a) are independently selected from the groupconsisting of H, (C₁-C₆)-alkyl, halo, CN and —CF₃;

[0178] Y is —O—, —S—, —SO—, —SO₂—, R⁵-heteroaryldiyl, R⁵-arylene or

[0179] p and q are independently 2-3;

[0180] Q and Q¹ are independently selected from the group consisting of

[0181] provided that at least one of Q and Q¹ is

[0182] R is R⁵⁻aryl, R⁵⁻-heteroaryl, R⁶—(C₂-C₆)alkenyl orR⁶—(C₂-C₆)alkynyl;

[0183] R² is R⁵⁻aryl, R⁵⁻heteroaryl, R⁵⁻aryl(C₁-C₆)alkyl orR⁵⁻heteroaryl(C₁-C₆)alkyl; or R²—Y is

[0184] U, V, and W are independently selected from the group consistingof N and CR¹, provided that at least one of U, V and W is CR¹;

[0185] n is 1, 2or 3; and

[0186] (a) A is C(R¹) and X is —C(R³)(R^(3a))—, —C(O)—, —O—, —S—, —SO—,—SO₂—, R⁴-arylene, R⁴-heteroaryldiyl, or —N(R⁹)—; or A is C(R¹), Y is abond, and X is —C(R³)(R^(3a))—, —C(O)—, —O—, —S—, —SO—, —SO₂—,R⁴-arylene, —N(R⁹)— or R⁴-heteroaryldiyl, provided that when X is—N(R⁹)— or R⁴-heteroaryldiyl, R² is not phenyl or phenyl-(C₁-C₆)alkyl;or

[0187] (b) A is N, X is —N(R⁹)—, Y is R⁵-arylene and R² is

[0188] or n is 2 or 3; and

[0189] (c) A is N and X is —C(R³)(R^(3a))—, —C(O)—, —O—, —S—, —SO—,—SO₂—, —N(R⁹)—, R⁴-arylene or R⁴-heteroaryldiyl; or A is N, Y is a bondand X is —C(O)—, —N(R⁹)—, R⁴-arylene or R⁴-heteroaryldiyl; or A is N, Yis —N(R^(9a))—, —C(O)N(R^(9a))— or —O—(CH₂)₂—N(R^(9a))—, and X is—N(R⁹)—; or A is N, X is —N(R⁹)—, and Y and R² together are

[0190] or n is 0; and

[0191] (d) A is N, Y is a bond, X is —N(R⁹)—, and R² is

[0192] (e) A is N, X is —N(R⁹)— and Y and R² together are

[0193] wherein Z is —C(O)—CH₂—, —C(O)—CH(C₁-C₆ alkyl)—, —CH₂—CH(C₁-C₆alkyl)-, or —CH(C₁-C₆ alkyl)-CH₂—;

[0194] R³ and R^(3a) are independently selected from the groupconsisting of H, —OH, C₁-C₆ alkyl, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl and di(C₁-C₆)alkylamino(C₁-C₆)alkyl;

[0195] R⁴ is 1-3 substituents selected from the group consisting of H,(C₁-C₆)alkyl, —OH, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo,—CF₃, and —CN;

[0196] R⁵ is 1-3 substituents independently selected from the groupconsisting of H, (C₁-C₆)alkyl, —OH, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)-alkoxy, halo, —CF₃, —CN,—NH₂, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, amino(C₁-C₆)-alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl,(C₁-C₆)alkanoyl-amino, (C₁-C₆)alkanesulfonylamino, (C₁-C₆)alkylthio,(C₁-C₆)alkylthio(C₁-C₆)alkyl, R⁶—(C₂-C₆)alkenyl, R⁶-(C₂-C₆)alkynyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy-C(O)-amino, orheterocycloalkyl(C₁-C₆)alkyl;

[0197] R⁶ is 1 to 3 substituents independently selected from the groupconsisting of H, —OH, (C₁-C₆)alkoxy and halo;

[0198] R⁷ and R^(7a) are independently selected from the groupconsisting of H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, R⁸-aryl andR⁸-heteroaryl, or an R⁷ and an R^(7a) substituent on the same carbon canform ═O;

[0199] R⁸ is 1 to 3 substituents independently selected from H,(C₁-C₆)alkyl, —OH, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo,—CF₃, and —CN;

[0200] R⁹ and R^(9a) are independently selected from the groupconsisting of H, (C₁-C₆)alkyl, hydroxy(C₂-C₆)alkyl,(C₁-C₆)alkoxy(C₂-C₆)alkyl, amino(C₂-C₆)alkyl,(C₁-C₆)alkylamino(C₂-C₆)alkyl, di(C₁-C₆)alkylamino(C₂-C₆)alkyl,halo-(C₃-C₆)alkenyl, CF₃-(C₁-C₆)alkyl, (C₃-C₆)alkenyl, (C₃-C₆)cycloalkyland (C₃-C₆)cycloalkyl-(C₁-C₆)alkyl; and

[0201] R¹⁰ is H, —C(O)—O—(C₁-C₆)alkyl, R⁵-aryl, —C(O)—(C₁-C₆)alkyl,—C(O)—(R⁵-aryl) or R⁵-aryl-(C₁-C₆)alkyl.

[0202] Preferred compounds of formula VIII are those wherein A is N. Ris preferably furyl. R^(1a) is preferably hydrogen. Another group ofpreferred compounds is that wherein X is —O—, —S—, —N(R⁹)— orR⁴-arylene, with compounds wherein X is —N(R⁹)— being more preferred. R⁹is preferably C₁-C₆ alkyl. Preferred definitions for Y are a bond orpiperazinyl. R² is preferably R⁵-aryl. When Y and/or R² is

[0203] Q is preferably N, Q¹ is preferably N, p and q are eachpreferably 2, each R⁷ and R^(7a) is preferably hydrogen, and R¹⁰ ispreferably —C(O)—O—(C₁-C₆)alkyl, —C(O)—(C₁-C₆)alkyl or —C(O)—(R⁵-aryl).R⁵ is preferably 1 or 2 substituents selected from the group consistingof H, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)-alkoxy, halo and —CF₃. R⁴ ispreferably H, halo or (C₁-C₆)alkyl. R³ and R^(3a) are preferablyindependently selected from H and (C₁-C₆)alkyl. R^(9a) is preferably Hor (C₁-C₆)alkyl. R⁶ is preferably hydrogen.

[0204] Preferred specific examples of compounds of formula VIII includecompounds of the formula

[0205] wherein R²—Y—(CH₂)_(n)—N(R⁹)— is as defined in the table:R²—Y—(CH₂)_(n)—N(R⁹)—

[0206] WO 01/02409 discloses useful adenosine A_(2a) receptor antagonistcompounds having the structural formula IX

[0207] wherein

[0208] X is O or S;

[0209] R₁ and R₂ are independently selected from hydrogen, alkyl, aryl,hydroxy, alkoky, aryloxy, cyano, nitro, CO₂R₇, COR₇, OCOR₇, CONR₇R₈,CONR₇NR₈R₉, OCONR₇R₈, NR₇R₈, NR₇COR₈, NR₇CONR₈R₉, NR₇CO₂R₈, NR₇SO₂R₈,NR₇CONR₈NR₉R₁₀, NR₇NR₈CO₂R₉, NR₇NR₈CONR₉R₁₀, NR₇SO₂NR₈R₉, SO₂R₇, SOR₇,SR₇ and SO₂NR₇R₈, or R₁and R₂ together form a carbonyl group (C═O), anoxime group (C═NOR₁₁), an imine group (C═NR₁₁) or a hydrazine group(C═NNR₁₁R₁₂), or R₁and R₂ together form a 5, 6 or 7 membered carbocyclicor heterocyclic ring;

[0210] R₃ is alkyl or aryl;

[0211] R₄, R₅ and R₆ ate independently selected from hydrogen, alkyl,aryl, halogen, hydroxy, nitro, cyano, alkoxy, aryloxy, CO₂R₇, COR₇,OCOR₇, SO₂R₇, SOR₇, SR₇, SO₂NR₇R₈, CONR₇R₈, CONR₇NR₈R₉, OCONR₇R₈, NR₇R₈,NR₇COR₈, NR₇CONR₈R₉, NR₇CO₂R₈, NR₇SO₂R₈, CR₇═NOR₈, NR₇CONR₈NR₉R₁₀,NR₇NR₈CO₂R₉, NR₇NR₈CONR₉R₁₀, SO₂NR₇NR₈R₉, NR₇SO₂NR₈R₉, NR₇NR₈SO₂R₉,NR₇NR₈CO₂R₉, NR₇NR₈R₉ and NR₇CSNR₈R₉, or R₅ and R₆ together form a 5, 6or 7 membered carbocyclic or heterocyclic ring; and

[0212] R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂ are independently selected fromhydrogen, alkyl and aryl, or a pharmaceutically acceptable salt orprodrug thereof.

[0213] The US patents and applications cited herein are incorporatedherein by reference. The adenosine A_(2a) receptor antagonists areprepared by known methods as described in the cited patents andapplications.

[0214] As used herein, “patient” means a mammal, especially a human.

[0215] It is contemplated that more than one adenosine A_(2a) receptorantagonist (e.g., 2 or 3) can be administered to treat EPS, dystonia,RLS or PLMS; preferably, one adenosine A_(2a) receptor antagonist isadministered.

[0216] Antipsychotic agents causing the EPS treated by adenosine A_(2a)receptor antagonists and for use in combination with adenosine A_(2a)receptor antagonists include typical and atypical antipsychotic agents.Typical antipsychotics include loxapine, haloperidol, chlorpromazine,prochlorperazine and thiothixene. Atypical antipsychotics includeclozapine, olanzapine, loxapine, quetiapine, ziprasidone andrisperidone.

[0217] Tricyclic antidepressants causing dystonia treated by adenosineA_(2a) receptor antagonists include perphenazine, amitriptyline,desipramine, doxepin, trimipramine and protriptyline. Anticonvulsantswhich may cause dystonia, but which also may be useful in treating ERLSor PLMS include phenytoin, carbamazepine and gabapentin.

[0218] Dopamine agonists useful in treating RLS and PLMS includepergolide, pramipexole, ropinerole, fenoldopam and cabergoline.

[0219] Opioids useful in treating PRLS and PLMS include codeine,hydrocodone, oxycodone, propoxyphene and tramadol.

[0220] Benzodiazepines useful in treating PRLS and PLMS includeclonazepam, triazolam and temazepam.

[0221] The antipsychotics, tricyclic antidepressants, anticonvulsants,dopamine agonists, opioids and benzodiazepines are commerciallyavailable and are described in the literature, e.g., in The Physicians'Desk Reference (Montvale: Medical Economics Co., Inc., 2001).

[0222] It is contemplated that two or more A_(2a) receptor antagonistscould be administered in combination with one or more other agents(e.g., antipsychotics, tricyclic antidepressants, anticonvulsants,dopamine agonists, opioids or benzodiazepines), although administrationof one A_(2a) antagonist in combination with one other agent ispreferred for each of the indications. While administration of separatedosage forms of the A_(2a) antagonist(s) and the other agent(s) arepreferred, it is also contemplated that the other agent(s) could becombined in a single dosage form with the A_(2a) receptor antagonist(s)for the treatment or prevention of EPS, dystonia, RLS or PLMS.

[0223] Preferred adenosine A2a antagonists are those described in U.S.Pat. No. 6,630,475.

[0224] A particularly preferred compound of the invention is Compound Aof the formula

[0225] or a pharmaceutically acceptable salt or solvate thereof,disclosed in U.S. Pat. No. 6,630,475 and listed as the first compound inthe table of compounds of structure I.

[0226] Compounds useful in the method of the invention will show utilityas adenosine A_(2a) receptor antagonists in these assays.

[0227] Human Adenosine A_(2a) and A₁ Receptor Competition Binding AssayProtocol Membrane sources: A_(2a): Human A_(2a) Adenosine Receptormembranes, Catalog #RB-HA2a, Receptor Biology, Inc., Beltsville, Md.Dilute to 17 μg/100 μl in membrane dilution buffer (see below).

[0228] Assay Buffers: Membrane dilution buffer: Dulbecco's PhosphateBuffered Saline (Gibco/BRL)+10 mM MgCl₂.

[0229] Compound Dilution Buffer: Dulbecco's Phosphate Buffered Saline(Gibco/BRL)+10 mM MgCl₂ supplemented with 1.6 mg/ml methyl cellulose and16% DMSO. Prepared fresh daily.

[0230] Ligands: A_(2a): [3H]-SCH 58261, custom synthesis,AmershamPharmacia Biotech, Piscataway, N.J. Stock is prepared at 1 nM inmembrane dilution buffer. Final assay concentration is 0.5 nM.

[0231] A₁: [3H]-DPCPX, AmershamPharmacia Biotech, Piscataway, N.J. Stockis prepared at 2 nM in membrane dilution buffer. Final assayconcentration is 1 nM.

[0232] Non-Specific Binding:

[0233] A_(2a): To determine non-specific binding, add 100 nM CGS 15923(RBI, Natick, Mass.). Working stock is prepared at 400 μM in compounddilution buffer.

[0234] A₁: To determine non-specific binding, add 100 μM NECA (RBI,Natick, Mass.). Working stock is prepared at 400 μM in compound dilutionbuffer.

[0235] Compound Dilution:

[0236] Prepare 1 mM stock solutions of compounds in 100% DMSO. Dilute incompound dilution buffer. Test at 10 concentrations ranging from 3 μM to30 pM. Prepare working solutions at 4× final concentration in compounddilution buffer.

[0237] Assay Procedure:

[0238] Perform assays in deep well 96 well plates. Total assay volume is200 μl. Add 50 μl compound dilution buffer (total ligand binding) or 50μl CGS 15923 working solution (A_(2a) non-specific binding) or 50 μlNECA working solution (A₁ non-specific binding) or 50 μl of drug workingsolution. Add 50 μl ligand stock ([3H]-SCH 58261 for A_(2a), [3H]-DPCPXfor A₁). Add 100 μl of diluted membranes containing the appropriatereceptor. Mix. Incubate at room temperature for 90 minutes. Harvestusing a Brandel cell harvester onto Packard GF/B filter plates. Add 45μl Microscint 20 (Packard), and count using the Packard TopCountMicroscintillation Counter. Determine IC₅₀ values by fitting thedisplacement curves using an iterative curve fitting program (Excel).Determine Ki values using the Cheng-Prusoff equation.

[0239] Haloieridol-Induced Catalepsy in the Rat

[0240] Male Sprague-Dawley rats (Charles River, Calco, Italy) weighing175-200 g are used. The cataleptic state is induced by the subcutaneousadministration of the dopamine receptor antagonist haloperidol (1 mg/kg,sc), 90 min before testing the animals on the vertical grid test. Forthis test, the rats are placed on the wire mesh cover of a 25×43plexiglas cage placed at an angle of about 70 degrees with the benchtable. The rat is placed on the grid with all four legs abducted andextended (“frog posture”). The use of such an unnatural posture isessential for the specificity of this test for catalepsy. The time spanfrom placement of the paws until the first complete removal of one paw(descent latency) is measured maximally for 120 sec.

[0241] The selective A_(2A) adenosine antagonists under evaluation areadministered orally at doses ranging between 0.03 and 3 mg/kg, 1 and 4 hbefore scoring the animals.

[0242] In separate experiments, the anti-cataleptic effects weredetermined for the reference compound, L-DOPA (25, 50 and 100 mg/kg,ip),

[0243] For preparing pharmaceutical compositions from the compoundsuseful in the method of this invention, inert, pharmaceuticallyacceptable carriers can be either solid or liquid. Solid formpreparations include powders, tablets, dispersible granules, capsules,cachets and suppositories. The powders and tablets may be comprised offrom about 0.1 to about 99 percent active ingredient. Suitable solidcarriers are known in the art, e.g. magnesium carbonate, magnesiumstearate, talc, sugar, lactose. Tablets, powders, cachets and capsulescan be used as solid dosage forms suitable for oral administration.

[0244] For preparing suppositories, a low melting wax such as a mixtureof fatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

[0245] Liquid form preparations include solutions, suspensions andemulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injection.

[0246] Liquid form preparations may also include solutions forintranasal administration.

[0247] Aerosol preparations suitable for inhalation may includesolutions and solids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas.

[0248] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

[0249] The compounds useful in the method of the invention may also bedeliverable transdermally. The transdermal compositions can take theform of creams, lotions, aerosols and/or emulsions and can be includedin a transdermal patch of the matrix or reservoir type as areconventional in the art for this purpose.

[0250] Preferably the adenosine A_(2a) receptor antagonist and theantipsychotic are administered orally.

[0251] Preferably, the pharmaceutical preparation is in unit dosageform. In such form, the preparation is subdivided into unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

[0252] The quantity of adenosine A_(2a) receptor antagonist in a unitdose of preparation may be varied or adjusted from about 0.1 mg to 1000mg, more preferably from about 1 mg to 300 mg, according to theparticular application.

[0253] The actual dosage employed may be varied depending upon therequirements of the patient and the severity of the condition beingtreated. Determination of the proper dosage for a particular situationis within the skill of the art. Generally, treatment is initiated withsmaller dosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day if desired.

[0254] The amount and frequency of administration of the adenosineA_(2a) receptor antagonist useful in the method of the invention will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddosage regimen for an adenosine A_(2a) receptor antagonist is oraladministration of about 10 mg to 2000 mg/day preferably 10 to 1000mg/day, in two to four divided doses to provide relief from the effectsof EPS, dystonia, RLS or PLMS. The compounds are non-toxic whenadministered within this dosage range.

[0255] The doses and dosage regimen of the other agents used incombination with the adenosine A_(2a) receptor antagonists, i.e., theantipsychotics, tricycicic antidepressants, anticonvulsants, dopamineagonists, benzodiazepines, opioids, lithium or iron, will be determinedby the attending clinician in view of the approved doses and dosageregimen in the package insert, taking into consideration the age, sexand condition of the patient and the severity of the disease. Whenadministered in combination, the adenosine A_(2a) receptor antagonistand the other agent can be administered simultaneously or sequentially.This is particularly useful when the components of the combination arepreferably given on different dosing schedules, e.g., one component isadministered daily and the other every six hours, or when the preferredpharmaceutical compositions are different, e.g. one is preferably atablet and one is a capsule. It is therefore advantageous to provide theadenosine A_(2a) receptor antagonist and the other agent in a kitcomprising, in separate containers in a single package, pharmaceuticalcompositions for use in combination to treat or prevent EPS, dystonia,RLS or PLMS, wherein one container comprises a pharmaceuticalcomposition comprising an effective amount of an adenosine A_(2a)receptor antagonist in a pharmaceutically acceptable carrier, andwherein a separate container comprises a pharmaceutical compositioncomprising an effective amount of another agent appropriate to treat theindicated condition.

[0256] Those skilled in the art will recognize that a dosage form forone of the components of the combination can be modified to contain bothan adenosine A_(2a) receptor antagonist and another agent, e.g., anadenosine A_(2a) receptor antagonist and an antipsychotic or anadenosine A_(2a) receptor antagonist and a dopamine agonist.

[0257] The following example shows the use of adenosine A2a antagoniststo attenuate the Extra-Pyramidal Syndrome (EPS) displayed in cebusapella monkeys sensitized to the dopamine D₂ receptor antagonist,haloperidol.

EXAMPLE

[0258] A colony of seven Cebus apella monkeys that were previouslysensitized to the chronic effects of haloperidol, exhibit EPS whenadministered haloperidol acutely (0.3 mg/kg, p.o.). Compound A wasadministered orally (p.o.) at doses of 0.3-30 mg/kg, in conjunction withhaloperidol. The studies were conducted using a within-subjects designsuch that each monkey received all 6 treatments (vehicle and 5 doses ofCompound A) in a crossover, balanced design. In all the studies, thegroup of seven monkeys exhibited baseline levels of EPS when dosed withhaloperidol.

[0259] Compound A produced a dose-dependent reduction in the maximum EPSscore (FIG. 1A), as well as a dose-dependent delay in the onset of EPS(FIG. 1B). At a dose of 1 mg/kg, Compound A prevented the onset of EPSin one monkey, and delayed the onset of EPS by 1 hr. Compound A, at adose of 3 mg/kg, prevented the onset of EPS in two monkeys, and delayedthe onset of EPS by almost 2 hr in the remaining monkeys. At 10 and 30mg/kg, Compound A prevented the onset of EPS in three monkeys anddelayed the onset of EPS by an average of 2.3-2.9 hr.

[0260] Clinical guidelines for the treatment of RLS and PLMS have beenestablished: see A. L. Chesson et al, Sleep, 22, 7 (1999), p. 961-8.Efficacy of adenosine A_(2a) antagonists in treating RLS and PLMS can bedetermined by a method analogous to the clinical method described in theliterature for pramipexole and ropinerole by Weimerskirch et al, Annalsof Pharmacotherapy, 35, 5 (2001), p. 627-30.

[0261] While the present invention has been described in conjunctionwith the specific embodiments set forth above, many alternatives,modifications and variations thereof will be apparent to those ofordinary skill in the art. All such alternatives, modifications andvariations are intended to fall within the spirit and scope of thepresent invention.

We claim:
 1. A method for the treatment or prevention of Extra-PyramidalSyndrome or dystonia comprising administering a therapeuticallyeffective amount of an adenosine A2a receptor antagonist to a patient inneed thereof.
 2. The method of claim 1 wherein the adenosine A2aantagonist is a compound of the formula

or a pharmaceutically acceptable salt thereof, wherein R is R¹-furanyl,R¹-thienyl, R¹-pyridyl, R¹-pyridyl N-oxide, R¹-oxazolyl, R¹⁰-phenyl,R¹-pyrrolyl or C₄-C₆ cycloalkenyl; X is C₂-C₆ alkylene or —C(O)CH₂—; Yis —N(R²)CH₂CH₂N(R³)—, —OCH₂CH₂N(R²)—, —O—, —S—, —CH₂S—, —(CH₂)₂—NH—, or

and Z is R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl, R⁵-heteroaryl,diphenylmethyl, R⁶—C(O)—, R⁶—SO₂—, R⁶—OC(O)—, R⁷—N(R⁸)—C(O)—,R⁷—N(R⁸)—C(S)—,

phenyl-CH(OH)—, or phenyl-C(═NOR )—; or when Q is

Z is also phenylamino or pyridylamino; or Z and Y together are

R¹ is 1 to 3 substituents independently selected from hydrogen,C₁-C₆-alkyl, —CF₃, halogen, —NO₂, —NR¹²R¹³, C₁-C₆ alkoxy, C₁-C₆alkylthio, C₁-C₆ alkylsulfinyl, and C₁-C₆ alkylsulfonyl; R² and R³ areindependently selected from the group consisting of hydrogen and C₁-C₆alkyl; m and n are independently 2-3; Q is

R⁴ is 1-2 substituents independently selected from the group consistingof hydrogen and C₁-C₆alkyl, or two R⁴ substituents on the same carboncan form ═O; R⁵ is 1 to 5 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆alkoxy, —CN, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃, acetyl, —NO₂,hydroxy(C₁-C₆)alkoxy, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy,di-((C₁-C₆)-alkoxy)(C₁-C₆)alkoxy,(C₁-C₆)-alkoxy(C₁-C₆)alkoxy-(C₁-C₆)-alkoxy, carboxy(C₁-C₆)-alkoxy,(C₁-C₆)-alkoxycarbonyl(C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl(C₁-C₆)alkoxy, di-((C₁-C₆)alkyl)amino(C₁-C₆)alkoxy, morpholinyl, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-SO—(C₁-C₆)alkoxy, tetrahydropyranyloxy,(C₁-C₆)alkylcarbonyl(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)alkylcarbonyloxy(C₁-C₆)-alkoxy, —SO₂NH₂, phenoxy,

or adjacent R⁵ substituents together are —O—CH₂—O—, —O—CH₂CH₂—O—,—O—CF₂—O— or —O—CF₂CF₂—O— and form a ring with the carbon atoms to whichthey are attached; R⁶ is (C₁-C₆)alkyl, R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl,thienyl, pyridyl, (C₃-C₆)-cycloalkyl,(C₁-C₆)alkyl-OC(O)—NH—(C₁-C₆)alkyl-, di-((C₁-C₆)alkyl)aminomethyl, or

R⁷ is (C₁-C₆)alkyl, R⁵-phenyl or R⁵-phenyl(C₁-C₆)alkyl; R⁸ is hydrogenor C₁-C₆ alkyl; or R⁷ and R⁸ together are —(CH₂)_(p)-A-(CH₂)_(q),wherein p and q are independently 2 or 3 and A is a bond, —CH₂—, —S— or—O—, and form a ring with the nitrogen to which they are attached; R⁹ is1-2 groups independently selected from hydrogen, C₁-C₆ alkyl, hydroxy,C₁-C₆ alkoxy, halogen, —CF₃ and (C₁-C₆)alkoxy(C₁-C₆)alkoxy; R¹⁰ is 1 to5 substituents independently selected from the group consisting ofhydrogen, halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, —CN, —NH₂,C₁-C₆alkylamino, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃ and—S(O)₀₋₂(C₁-C₆)alkyl; R¹¹ is H, C₁-C₆ alkyl, phenyl, benzyl, C₂-C₆alkenyl, C₁-C₆ alkoxy(C₁-C₆)alkyl, di-((C₁-C₆)alkyl)amino(C₁-C₆)alkyl,pyrrolidinyl(C₁-C₆)alkyl or piperidino(C₁-C₆)alkyl; R¹² is H or C₁-C₆alkyl; and R¹³ is (C₁-C₆)alkyl-C(O)— or (C₁-C₆)alkyl-SO₂—.
 3. The methodof claim 2 wherein the adenosine A2a receptor antagonist is selectedfrom the group consisting of compounds of the formula

wherein R and Z-Y are as defined in the following table: Z—Y— R

or a pharmaceutically acceptable salt or solvate thereof.
 4. The methodof claim 3 wherein the adenosine A2a receptor antagonist is

or a pharmaceutically acceptable salt or solvate thereof.
 5. The methodof claim 1 for treating or preventing Extra-Pyramidal Syndrome.
 6. Themethod of claim 5 wherein the Extra-Pyramidal Syndrome has been causedby treatment with a typical antipsychotic agent or an atypicalantipsychotic agent.
 7. The method of claim 6 wherein the typicalantipsychotic agent is selected from the group consisting of loxapine,haloperidol, chlorpromazine, prochlorperazine and thiothixene, and theatypical antipsychotic agent is selected from the group consisting ofclozapine, olanzapine, loxapine, quetiapine, ziprasidone and risperidone8. The method of claim 5 further comprising administering anantipsychotic agent in combination with the adenosine A2a receptorantagonist.
 9. The method of claim 8 wherein the antipsychotic agent isa typical antipsychotic agent selected from the group consisting ofloxapine, haloperidol, chlorpromazine, prochlorperazine and thiothixene,or an atypical antipsychotic agent selected from the group consisting ofclozapine, olanzapine, loxapine, quetiapine, ziprasidone andrisperidone.
 10. A kit comprising, in separate containers in a singlepackage, pharmaceutical compositions for use in combination to treat orprevent EPS caused by treatment with antipsychotic agent, wherein onecontainer comprises a pharmaceutical composition comprising an effectiveamount of an adenosine A_(2a) receptor antagonist in a pharmaceuticallyacceptable carrier, and wherein, a separate container comprises apharmaceutical composition comprising an effective amount of anantipsychotic agent.
 11. A method of claim 1 for the treatment ofidiopathic dystonia or dystonia caused by the use of cocaine.
 12. Themethod of claim 1 for the treatment or prevention of dystonia caused bytreatment with a tricyclic antidepressant, lithium or an anticonvulsant.13. The method of claim 12 further comprising administering a tricyclicantidepressant, lithium or an anticonvulsant in combination with theadenosine A2a receptor antagonist.
 14. The method of claim 13 whereinthe tricyclic antidepressant is selected from the group consisting ofperphenazine, amitriptyline, desipramine, doxepin, trimipramine andprotriptyline, and the anticonvulsant is selected from the groupconsisting of phenytoin, carbamazepine and gabapentin.
 15. A kitcomprising, in separate containers in a single package, pharmaceuticalcompositions for use in combination to treat or prevent dystonia causedby treatment with a tricyclic antidepressant, lithium or ananticonvulsant, wherein one container comprises a pharmaceuticalcomposition comprising an effective amount of an adenosine A_(2a)receptor antagonist in a pharmaceutically acceptable carrier, andwherein, a separate container comprises a pharmaceutical compositioncomprising an effective amount of a tricyclic antidepressant, lithium oran anticonvulsant.
 16. A method of treating restless leg syndrome orperiodic leg movement in sleep comprising administering atherapeutically effective amount of an adenosine A2a receptor antagonistto a patient in need thereof.
 17. The method of claim 16 wherein theadenosine A2a antagonist is a compound of the formula

or a pharmaceutically acceptable salt thereof, wherein R is R¹-furanyl,R¹-thienyl, R¹-pyridyl, R¹-pyridyl N-oxide, R¹-oxazolyl, R¹⁰-phenyl,R¹-pyrrolyl or C₄-C₆ cycloalkenyl; X is C₂-C₆ alkylene or —C(O)CH₂—; Yis —N(R²)CH₂CH₂N(R³)—, —OCH₂CH₂N(R²)—, —O—, —S—, —CH₂S—, —(CH₂)₂—NH—, or

and Z is R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl, R⁵-heteroaryl,diphenylmethyl, R⁶—C(O)—, R⁶—SO₂—, R⁶—OC(O)—, R⁷—N(R⁸)—C(O)—,R⁷—N(R⁸)—C(S)—,

phenyl-CH(OH)—, or phenyl-C(═NOR²)—; or when Q is

Z is also phenylamino or pyridylamino; or Z and Y together are

R¹ is 1 to 3 substituents independently selected from hydrogen,C₁-C₆-alkyl, —CF₃, halogen, —NO₂, —NR¹²R¹³, C₁-C₆ alkoxy, C₁-C₆alkylthio, C₁-C₆ alkylsulfinyl, and C₁-C₆ alkylsulfonyl; R² and R³ areindependently selected from the group consisting of hydrogen and C₁-C₆alkyl; m and n are independently 2-3; Q is

R⁴ is 1-2 substituents independently selected from the group consistingof hydrogen and C₁-C₆alkyl, or two R⁴ substituents on the same carboncan form ═O; R⁵ is 1 to 5 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆alkoxy, —CN, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃, acetyl, —NO₂,hydroxy(C₁-C₆)alkoxy, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy,di-((C₁-C₆)-alkoxy)(C₁-C₆)alkoxy,(C₁-C₆)-alkoxy(C₁-C₆)alkoxy-(C₁-C₆)-alkoxy, carboxy(C₁-C₆)-alkoxy,(C₁-C₆)-alkoxycarbonyl(C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl(C₁-C₆)alkoxy,di-((C₁-C₆)alkyl)amino(C₁-C₆)alkoxy, morpholinyl, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-SO—(C₁-C₆)alkoxy, tetrahydropyranyloxy,(C₁-C₆)alkylcarbonyl(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)alkylcarbonyloxy(C₁-C₆)-alkoxy, —SO₂NH₂, phenoxy,

or adjacent R⁵ substituents together are —O—CH₂—O—, —O—CH₂CH₂—O—,—O—CF₂—O— or —O—CF₂CF₂—O— and form a ring with the carbon atoms to whichthey are attached; R⁶ is (C₁-C₆)alkyl, R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl,thienyl, pyridyl, (C₃-C₆)-cycloalkyl,(C₁-C₆)alkyl-OC(O)—NH—(C₁-C₆)alkyl-, di-((C₁-C₆)alkyl)aminomethyl, or

R⁷ is (C₁-C₆)alkyl, R⁵-phenyl or R⁵-phenyl(C₁-C₆)alkyl; R⁸ is hydrogenor C₁-C₆ alkyl; or R⁷ and R⁸ together are —(CH₂)_(p)-A-(CH₂)_(q),wherein p and q are independently 2 or 3 and A is a bond, —CH₂—, —S— or—O—, and form a ring with the nitrogen to which they are attached; R⁹ is1-2 groups independently selected from hydrogen, C₁-C₆ alkyl, hydroxy,C₁-C₆ alkoxy, halogen, —CF₃ and (C₁-C₆)alkoxy(C₁-C₆)alkoxy; R¹⁰ is 1 to5 substituents independently selected from the group consisting ofhydrogen, halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, —CN, —NH₂,C₁-C₆alkylamino, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃ and—S(O)₀₋₂(C₁-C₆)alkyl; R¹¹ is H, C₁-C₆ alkyl, phenyl, benzyl, C₂-C₆alkenyl, C₁-C₆ alkoxy(C₁-C₆)alkyl, di-((C₁-C₆)alkyl)amino(C₁-C₆)alkyl,pyrrolidinyl(C₁-C₆)alkyl or piperidino(C₁-C₆)alkyl; R¹² is H or C₁-C₆alkyl; and R¹³ is (C₁-C₆)alkyl-C(O)— or (C₁-C₆)alkyl-SO₂—.
 18. Themethod of claim 16 further comprising administering levodopa/carbidopa,levodopa/benserazide, a dopamine agonist, a benzodiazepine, an opioid,an anticonvulsant or iron in combination with the adenosine A2a receptorantagonist.
 19. A kit comprising, in separate containers in a singlepackage, pharmaceutical compositions for use in combination to treat orprevent restless leg syndrome or periodic leg movement in sleep, whereinone container comprises a pharmaceutical composition comprising aneffective amount of an adenosine A_(2a) receptor antagonist in apharmaceutically acceptable carrier, and wherein a separate containercomprises a pharmaceutical composition comprising an effective amount ofa dopamine agonist, benzodiazepine, opioid, anticonvulsant or iron.